News beyond our pages
Authors: Marc E. Rothenberg, Jean Bousquet
Journal: Journal of Allergy and Clinical Immunology (2023)

Despite its universality, the molecular mechanisms underlying the aging process remain poorly understood. Liu et al (Cell 2023;186:287-304.e26; https://doi.org/10.1016/j.cell.2022.12.017) uncovered a positive feedback loop between the activation of dormant endogenous retroviruses and aging. More specifically, cellular senescence induced the reactivation and accumulation of the endogenous retrovirus HERVK. This in turn led to the production and extracellular release of retrovirus-like particles (RVLPs) that induced cellular senescence in neighboring young cells in a paracrine fashion. Neutralizing antibodies directed against RVLPs prevented this senescence-promoting effect. Finally, endogenous retrovirus activation was observed in the tissues of aged mice and primates, including humans. Collectively, these results support further study into preventing the resurrection of endogenous retroviruses to slow the aging process. Figure reproduced under Creative Commons license CC-BY_SA 4.0, attribution: users Rebelo-Marques, De Sousa Lages, Andrade, Ribeiro, Mota-Pinto, Carrilho and Espregueira-Mendes, via Wikimedia Commons. We asked corresponding author Guang-Hui Liu, PhD, of the State Key Laboratory of Membrane Biology, Institute of Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China, to comment on the study. He writes, “Our study uncovers epigenetic derepression of endogenous retrovirus as a hallmark and driving force of aging, which provides new insights into understanding the theory of programmed and transmissible aging, and into developing clinical strategies to evaluate and combat aging.” In order to clarify how oral immunotherapy (OIT) induces sustained tolerance in IgE-mediated food allergy, LaHood et al (J Clin Invest 2023;133:e164501; https://doi.org/10.1172/JCI164501) examined the allergen-specific antibody repertoires of human patients with either sustained or transient positive responses to peanut OIT. The authors focused on Ara h 2, the most clinically relevant peanut allergen, and identified and structurally characterized specific antibody epitopes enriched among sustained, but not transient, responders. Notably, antibodies recognizing these unique epitopes functionally suppressed IgE-mediated effector cell activation. These results have helped clarify molecular determinants of OIT-induced antibody-mediated tolerance and will likely inform further investigations involving the use of neutralizing antibodies in the treatment of IgE-mediated food allergy.Suppressed IgE-mediated effector cell activation Suppressed IgE-mediated effector cell activation Dellon et al (N Engl J Med 2022;387:2317-30; https://doi.org/10.1056/NEJMoa2205982) conducted a randomized, placebo-controlled, phase 3 trial to examine the efficacy of dupilumab, an mAb that blocks the signaling of both IL-4 and IL-13 in adult and adolescent patients with active eosinophilic esophagitis (EoE). In 2 independent patient cohorts, weekly subcutaneous dupilumab treatment improved both symptom control and histologic outcomes at week 24 as compared to placebo. Dupilumab was generally well-tolerated. These findings demonstrate that dupilumab is effective in treating EoE and formed the basis for its recent approval by the Food and Drug Administration. Figure reproduced under Creative Commons license CC-BY_SA 3.0, attribution: user Samir at the English-language Wikipedia, via Wikimedia Commons. We asked corresponding author Evan S. Dellon, MD, MPH, of the University of North Carolina School of Medicine, Chapel Hill, North Carolina, to comment on the study. He writes, “This study showed dupilumab leads to notable improvements across multiple aspects of EoE disease activity, including symptomatic, histologic, endoscopic, and molecular features, as compared to placebo. It is a major milestone for patients suffering from this condition to have the first FDA-approved medication to treat EoE in the US.” Strong genetic associations exist between impaired transforming growth factor-β signaling and risk of developing eosinophilic esophagitis (EoE). Laky et al (Sci Immunol 2023;8:eabp9940; https://doi.org/10.1126/sciimmunol.abp9940) discovered that expression of a loss-of-function variant of transforming growth factor-β receptor 1 (TGFβR1) identified in human atopic patients induced spontaneous development of EoE-like disease in mice. Notably, this EoE-like phenotype was lymphocyte-independent. Mechanistic studies revealed that expression of this loss-of-function TGFβR1 variant in epithelial cells resulted in hyperproliferation, defective differentiation, and overproduction of proinflammatory and chemotactic soluble mediators. In total, these results demonstrate an innate, epithelial cell-intrinsic role for TGFβ signaling in restraining esophageal allergic inflammation. Figure reproduced under Creative Commons license CC-BY_SA 3.0, attribution: user Nephron, via Wikimedia Commons. We asked corresponding author Pamela A. Guerrerio, MD, PhD, of the Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, Maryland, to comment on the study. She writes, “Epithelial dysfunction is a common feature of many allergic diseases including EoE, but whether this is a driving factor or a secondary consequence of allergic inflammation is not clear. Our work suggests that epithelial cell intrinsic defects can initiate localized allergic inflammation, and that TGFβ is a key player in this process independent of its role in regulating adaptive immune responses.” Modulation of the commensal gut microbiome has the potential to revolutionize treatment of human disease. Wang et al (Nat Biomed Eng 2023;7:38-55; https://doi.org/10.1038/s41551-022-00972-5) demonstrated therapeutic benefit of intragastric delivery of butyrate-containing polymeric micelles in experimental murine models of colitis and peanut allergy. Mechanistically, butyrate was released in localized regions of the small and large intestines and increased the abundance of beneficial Clostridium species to restore intestinal immune homeostasis. These findings highlight targeted nanoscale intestinal delivery of short chain fatty acids, such as butyrate, as a potential therapeutic strategy to treat allergic and inflammatory disease. Further study, including the potential generalizability to other microbial metabolites, is warranted. Figure reproduced under Creative Commons license CC-BY_SA 4.0, attribution: user Amanda Crochet, via Wikimedia Commons.Jeffrey A. Hubbell and Cathryn R. NaglerView Large Image Figure ViewerDownload Hi-res image Download (PPT) We asked corresponding authors Jeffrey A. Hubbell, PhD, and Cathryn R. Nagler, PhD, of the Pritzker School of Molecular Engineering, University of Chicago, Chicago, Illinois, to comment on the stydy. Dr Hubbel writes, “The delivery system allows plug-and-play coupling of a variety of microbial metabolites and other small molecules in a manner consistent with oral administration and chronic care.” Dr Nagler adds, “This allows us to employ knowledge of the function of the microbiome in preventing allergy and gut inflammation, yet without the complexity of actual administration of microbial therapies.”News items were written by medical writer Jared Travers, MD, PhD. News items were written by medical writer Jared Travers, MD, PhD.